Atherothrombosis describes the acute thrombotic event that occurs after rupture of an atherosclerotic plaque. It often leads to arterial occlusion and subsequent clinical manifestations of myocardial infarction, stroke, and sudden death. Tissue factor (TF) is the receptor for plasma factor VIIa (FVIIa) and, once formed, the TF:FVIIa complex activates the coagulation cascade. TF is present at high levels within atherosclerotic lesions and is also present on circulating monocytes and microparticles in patients with advanced cardiovascular disease (CVD). Formation of the TF:FVIIa complex plays a central role in atherothrombosis. This review will describe the cellular sources of TF, the potential of TF-positive microparticles as a biomarker of thrombotic risk, and current pharmacologic approaches to inhibit TF as a therapeutic intervention in patients with CVD.